The immune system is a highly sophisticated bio-circuit used by the body to discriminate non-self (e.g., foreign organisms or substances) from self. The detection of non-self in the body can result in inflammation, in which various cellular and molecular components are orchestrated to respond to potentially harmful events caused by the non-self organism or substance. Although the inflammatory process helps to protect the body from foreign attack, de-regulation of the immune system can lead to negative consequences such as self attack, e.g., autoimmune disease. By altering the function of inflammatory molecules such as chemokines, it may be possible to reduce the initiation and progression of disorders relating to immune/inflammatory responses.
Chemokines are a family of small (8-10 kDa) proteins that play a pivotal role in inflammation. During the inflammatory process, chemokines are produced locally at the site of the noxious stimulus and work as central players to recruit immune cells that express their cognate receptors, seven trans-membrane G protein-coupled receptors (GPCRs). CCL20, alternatively named liver and activation-regulated chemokine (LARC), macrophage inflammatory protein-3 alpha (MIP-3α), or Exodus-1, is a soluble chemokine that is expressed by epithelial cells. Epithelial keratinocytes and synovium-lining cells are known to produce large amounts of CCL20 during homeostatic as well as inflammatory and pathological conditions such as cancer, psoriasis, and rheumatoid arthritis. The cognate receptor for CCL20 is CC chemokine receptor 6 (CCR6); CCL20 is the only chemokine known to interact with CCR6. In response to the CCL20 signal, immune cells possessing CCR6, such as immature dendritic cells (DC), effector/memory T-cells, and B-cells, migrate and infiltrate the surrounding tissues, thus activating the inflammatory cascade.
Because CCL20 expression is significantly enhanced in inflammation induced by inflammatory cytokines such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), the CCL20-CCR6 interaction is thought to play a role in pathological inflammatory processes.
Rheumatoid Arthritis (RA) is one of the most common autoimmune diseases. The first sign of RA is often synovitis, which manifests as a swollen, painful joint. Although the specific factors that initiate synovitis remain unknown, synovium lining epithelial cells and synovial fibroblasts are thought to be primary inducers of the inflammatory reaction. Synovial fluid from RA patients effectively chemo-attracts human monocytes and pro-inflammatory T helper 17 (Th17) cells, which then induce and exacerbate the RA inflammatory process. Because reactive synovial cells are capable of producing large amounts of CCL20 (particularly under the influence of IL-1β and TNF-α), while CCR6 is the major receptor of Th17 cells, the CCL20-CCR6 interaction is thought to play a key role in the inflammatory process.
The CCL20-CCR6 interaction may also play an important role in certain types of dermatitis. Psoriasis, for example, initiates with a noxious psoriatic event in the skin (induced by environmental and/or genetic factors) followed by infiltration of Th17 cells. Because CCR6 is expressed on the surface of Th17 cells, B cells, dendritic cells, and tissue damaging effector T cells, CCL20 may represent the main chemoattractant for these cell types in psoriasis. Further evidence for the importance of the CCL20-CCR6 interaction can be found in studies using an interleukin 23 (IL-23)-induced mouse model of psoriasis (Hedrick et al., J. Clin. Invest. 119:2317-2329 (2009)). In this model, injection of IL-23 causes interleukin 22 (IL-22)-dependent psoriatic inflammation. However, Ccr6−/− mice did not exhibit psoriasis-like symptoms when injected with IL-23, indicating that CCR6 is required for the development of psoriasis.
Human keratinocytes can produce large amounts of CCL20, especially under the influence of the Th17-derived cytokines interleukin 17 (IL-17), IL-22, and TNF-α. While CCL20 and CCR6 are rarely detected in normal skin, both exhibit increased expression levels in atopic dermatitis and pustular psoriasis. Strong induction of CCL20 and accumulation of CCR6+ cells can be observed in microscopic immunohistochemical analysis of human dermatitis lesions. These observations provide additional evidence for the role of CCL20 and CCR6 in the dermatitis inflammatory process.
Currently available MAb biologics for treating immune disorders can be roughly classified into three groups: inhibitors of immunostimulatory cytokines (e.g., anti-TNF-α MAbs), immune cell eliminators (e.g., anti-CD20 MAbs), and blockers of accessory molecules (e.g. Abatacept). These biologics may be useful in the treatment of inflammatory diseases; however, due to primary non-responsiveness or a gradual decline in response rate to these treatments, there is an urgent need for alternative biologics with novel mechanisms of action to meet the medical needs of patients with, e.g., CCL20/CCR6-mediated disorders. The antibodies of the subject invention represent such alternative biologics.